This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DNA templates for transcription are continuously damaged by extrinsic factors such as radiation and chemical agents, as well as by products of endogenous metabolic processes. DNA damage impairs transcription and triggers a variety of cellular responses, including DNA repair pathways, signaling pathways that activate cell cycle checkpoints, and apoptosis. Maintenance of DNA integrity and high fidelity in transcription are crucial for life processes. Defects in DNA repair or the processing of DNA damage can lead to cancer or other human diseases. The goal of proposed research is to determine the structures of protein complexes involving in DNA lesion processing during transcription and understand the mechanism of these cellular processing pathways through an integrated multidisciplinary combination of structural and biochemical methods. The results will have implications for transcriptional regulation, DNA damage recognition, DNA repair, and chemotherapy for cancer and other human diseases.